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- W4313458981 abstract "Abstract As chronic antigenic stimulation from infection and autoimmunity are features of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T cell differentiation, and explain how environmental exposures modify clinical phenotypes conferred by single gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while CD57 + CD4 + T cells are normally rare in the circulation, we found that they are increased in patients with PAD, and markedly by CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57 + CD4 + T cells from blood and tonsil. Circulating CD57 + CD4 + T cells (CD4cyt) exhibit a cytotoxic transcriptome similar to CD8 + effectors, can kill B cells, and inhibit B cell responses. CTLA4 restrains the formation of CD4cyt. While CD57 also marks an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset has a precursor of exhaustion transcriptomic signature marked by TCF7 , TOX , ID3 , and constitutive expression of CTLA4, and are robust to becoming cytotoxic even after CTLA4 inhibition. Thus, CD57 + CD4 + T cell phenotypes of cytotoxicity and exhaustion are compartmentalized between blood and germinal centres. CTLA4 is a key modifier of CD4 + T cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated in CTLA4 deficiency by the environmental stimulus of infection." @default.
- W4313458981 created "2023-01-06" @default.
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- W4313458981 date "2023-01-03" @default.
- W4313458981 modified "2023-10-16" @default.
- W4313458981 title "CTLA4 protects against maladaptive cytotoxicity during differentiation of effector and follicular CD4+ T cells" @default.
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